This invention relates to certain benzothiophenes, compositions containing those compounds, and methods of their use.
The enzyme 5-lipoxygenase (5-LO) catalyzes the first step of a biochemical synthesis pathway by which arachidonic acid is converted into leukotrienes. Numerous and extremely potent biological activities have been associated with leukotrienes. Leukotrienes have been implicated as important mediators in a variety of disease states such as asthma, arthritis, psoriasis, ischemia, allergy, adult respiratory distress syndrome (ARDS), and inflammatory bowel disease (IBD).
Considerable efforts have been directed toward the control of leukotriene biosynthesis. Generally, research efforts directed toward the control of leukotriene biosynthesis have been directed toward the discovery of inhibitors of the 5-LO pathway and, in particular, 5-LO specific inhibitors.
In U.K. Patent Application GB 2,196,629 certain ring substituted-N-hydroxy-N-substituted benzamide and cinnamamide compounds are disclosed as antileukotriene agents. The ring substituent may be a group having the Formula (Ra) (Rb) C.dbd.CH-- where (Ra) (Rb)C.dbd. is an unsaturated aliphatic hydrocarbylene group containing 3 to 19 carbon atoms, a group having the formula R.sub.3 --C.dbd.C-- where R.sub.3 is a hydrogen atom or a saturated or unsaturated aliphatic hydrocarbyl group containing 1 to 18 carbon atoms or a group having the formula R.sub.4 --S-- where R.sub.4 is an aliphatic hydrocarbyl group containing 1 to 20 carbon atoms. The N-substituent may be a C.sub.1 -C.sub.6 alkyl group, a C.sub.3 -C.sub.7 cycloalkyl group or a substituted or unsubstituted aryl group.
In European Patent Application 0196184 certain aryl compounds are disclosed which include, among many others, certain cinnamohydroxamic acid analogs and certain N-hydroxyureas in Examples 81-91. Certain urea based or urea containing compounds that are said to inhibit lipoxygenase are disclosed in EPO 0292699; EPO 0279281; and EPO 0279263. These references contain a recognition of the importance of 3- 2-(halo-phenylthio)phenyl!prop-2-enyl subsituted on a urea skeleton.
In WO 90/12008 certain unsubstituted and substituted phenyl, naphthyl and thienyl N-hydroxy ureas are disclosed as inhibitors of 5- and 12-lipoxgenase. The preparation and biological activity for a number of such derivatives is disclosed. The present invention is directed to the discovery that a select group of N-hydroxy-N- 3- 2- 4-halophenylthio)phenyl!-prop-2-enyl!ureas are extremely potent 5-LO inhibitors.
Another important compound of the thienyl N-hydroxyurea class is (I)-N-(1-benzo B!thien-2-ylethyl)-N-hydroxyurea, i.e., Zileuton. The synthesis of Zileuton is described in U.S. Pat. No. 4,873,259 and its experimental pharmacology and clinical evaluation are reviewed in "Drugs of the Future 1993", 18(7), P. 616-618.
The compounds of the present invention, as defined herein, are inhibitors of 5-LO and have useful medical prophylactic and therapeutic properties.